Identification of adjunctive, oral pharmacotherapies to treat T1D has been limited by risk of DKA. TTP399, an oral hepatoselective GKA, significantly improves glycemia in individuals with T1D compared to placebo. This double-blind, randomized, placebo-controlled, Phase 1 mechanistic study examined whether TTP399 decreases ketogenesis during insulin withdrawal.
Individuals with T1D (n=23) using insulin pump therapy were randomized to TTP399 or placebo for 7-days after which an insulin withdrawal test (IWT) was performed. Insulin pumps were disconnected for up to hours to induce ketogenesis.
TTP399 significantly reduced fasting glucose (-27.6 vs. -4.4 mg/dL, p = 0.03) . During the treatment period, adverse events were fewer in TTP399-treated subjects. No hypoglycemic events <54mg/dL were observed in the TTP399 group compared with 2 subjects in the placebo group. Following insulin withdrawal, no significant differences in mean duration of IWT or beta-hydroxybutyrate (BOHB) at termination were observed between treatment groups (Figure 1A) . Serum bicarbonate was numerically higher and urine acetoacetate was qualitatively lower in TTP399-treated subjects (Figure 1A) . No patients on TTP399 met prespecified criteria for DKA while 43% of subjects on placebo did (Figure 1B, p = 0.03) .
These data suggest that TTP399 treatment improves glucose control with no increased risk of DKA.
K.Klein: None. S.C.Boeder: Consultant; Cecelia Health, Research Support; Dexcom, Inc., Lilly. J.L.Freeman: Employee; vTv Therapeutics, Stock/Shareholder; vTv Therapeutics. S.Madduri: None. E.R.Giovannetti: None. C.Valcarce: Employee; vTv Therapeutics. J.B.Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S, Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. J.Pettus: Advisory Panel; Lilly, MannKind Corporation, Novo Nordisk, Sanofi, Consultant; Carmot Therapeutics, Inc., Diasome.